Complement Receptor Deficiency 

Updated: Apr 13, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD 

Overview

Background

The complement system, interacting with its regulatory molecules and cellular receptors, plays a central role in the induction and regulation of immunity.

Complement receptors have only been identified in the last 2 decades. They have a wide cellular and tissue distribution, and play a major role in the mediation of biological responses. Their function in the transporting, processing, and clearing of immune complexes, as well as in neutrophil functions, is pivotal. Effector proteins interacting with the Fc portion of immunoglobulin M (IgM) include complement and complement receptors.[1]

Partial or complete deficiencies of the components of the complement system, including its receptors and regulatory proteins, are now described in humans and may be of a genetic or familial origin or acquired.

Research with animals, particularly mice with specifically targeted mutations, has allowed better comprehension of the specific mechanisms involved in deficiency states and the resulting clinical manifestations and/or associated diseases. Mice with C5a receptor–deficient dendritic cells promote induction of Treg and Th17 cells.[2] T cell–derived complement C3a and CD46 activation is required for Th1 induction.[3]

Note the image below, as well as the article Pediatric Complement Receptor Deficiency may be helpful.

Protein defects. Protein defects.

Pathophysiology

Four distinct complement receptors, CR1, CR2, CR3, and CR4, have been described for the surface-bound complement fraction C3 and its cleavage fragments. Activation of the complement cascade always leads to the enzymatic cleavage of complement fraction C3, which is important in host defense to bacterial infections and phagocytosis.

Complement and complement receptors play a critical role in immune defense by initiating the rapid destruction of invading microorganisms, amplifying the innate and adaptive immune responses, and mediating solubilization and clearance of immune complexes. Defects in the expression of complement or complement receptors may result in loss of tolerance to self-proteins and the development of immune complex–mediated autoimmune diseases such as systemic lupus erythematosus (SLE).[4]

Receptors for the anaphylatoxins C3a and C5a have also been identified.

CR1/CD35 and CR2/CD21 are major receptors for activated fragments of C3. They are single-chain molecules present on host cellular membranes and belong to the complement control protein family. They are encoded by separate but linked genes termed regulation of complement activation (RCA) genes, located on the q32 region of chromosome 1. The receptors are widely expressed in humans. They tend to enhance the effects of complement and are highly important in the binding of opsonized immune complexes on B cells.

CR1/CD35 is the receptor for C3b. The CR1 receptor preferentially binds C3b that is covalently attached to immune complexes, and it has a weaker affinity for bound C4b and iC3b. It is a single-chain membrane glycoprotein of approximately 200 kd that has 4 allotypic forms on myeloid cells (eg, erythrocytes, granulocytes, monocytes), lymphoid cells (mostly B cells), follicular dendritic cells, and glomerular podocytes.

The density of CR1 receptors on cell surfaces varies with the cell type and with the activation of the cell for neutrophils and monocytes. Because of their high numbers, red blood cells express an average of 90% of the CR1 receptors despite their having a lower number of antigenic sites per cell. Among healthy individuals, the number of CR1 receptors on the red blood cells varies widely, yet the phenotypic expression, regulated by 2 codominant alleles, is stable.

CR1 has an important role in complement and immune regulation; in phagocytosis and clearance of immune complexes; and in mediating adherence of opsonized bacteria, viruses, and immune complexes. Opsonized immune complexes (coated by C3b and C4b) bind to CR1, mostly on red blood cells, and are cleared through the liver where they can be transferred to CR3-bearing phagocytes and endocytosed. CR1 and CR2 have been shown to influence the immune environment in a B-cell receptor–independent manner.[5]

CR1 also regulates complement activation by acting as a cofactor for factor I in the cleavage and degradation of bound C3b and C4b to its inactive forms. It also is involved in the generation of ligands for CR2 and CR3, which are believed to be involved in the clearance of immune complexes.

CR2/CD21 interacts with C3b degradation products C3dg and C3d and can act synergistically with the B-cell antigen receptor (BCR) in B-cell activation. CR2/CD21 is a single-chain membrane glycoprotein of approximately 150 kd. C3d-or C3dg-bearing immune complexes can bind to CR2. C3dg and C3d also can bind to the surface of bacteria and fungi, allowing CR2 on B cells and follicular dendritic cells to present the organisms for immune triggering.

CR2 is expressed primarily on lymphoid cells (B and T lymphocytes) and follicular dendritic cells. CR2 plays an important role in the presentation of antigen to specific B and T cells and in the control of B-cell proliferation. Evidence clearly suggests that CR2 is involved in the induction of a primary humoral response. Humoral antibody response is regulated by the direct effect of C3dg on the cell cycle of B cells and by the dependence of the B-cell response to a soluble T-cell–dependent antigen on iC3b and C3dg.

A second component of CR2 binds the Epstein-Barr virus (EBV). EBV requires the CR2 receptor to enter the cell. EBV is an oncogenic herpes virus that is implicated in the pathogenesis of acute mononucleosis, Burkitt lymphoma, and nasopharyngeal carcinoma. It infects and immortalizes B lymphocytes by binding CR2 in vitro.

CR3 (CD11b/18) and CR4 (CD11c/18) both bind to iC3b and promote adhesive interactions of leucocytes with the vascular endothelium. The receptors may act as ligands for adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1)/CD54 for CR3. They are present on phagocytic cells. Both are members of the beta integrin family. They are heterodimers made of an identical 95-kd beta chains (CD18) and different alpha chains (165 kd for CD11b in CR3 and 150 kd for CD11c in CR4). The beta subunit is shared by another plasma membrane protein lymphocyte function associated antigen (LFA-1 or CD11a/18). CR3 (CD11b/18) is found on eosinophils, basophils, monocytes, natural killer (NK) cells, most tissue macrophages, and neutrophils. It has a role in cellular adhesion and aggregation, particularly that of neutrophils and monocytes. CR4 (CD11c/18) is similar to CR3 structurally, has a similar affinity for iC3b, and is found on neutrophils.

CR3 and CR4 have an important role in host resistance to infection. iC3b-coated immune complexes have a high affinity for the CR3 receptor on phagocytic cells of the liver and spleen, to where they are transported and degraded.

C3a is a potent anaphylatoxin and proinflammatory mediator generated by proteolytic cleavage of C3 in complement cascade activation. It is involved in the secretion of histamine, smooth muscle contraction, and chemoattraction of eosinophils and mast cells. Findings from recent reports have paradoxically demonstrated an anti-inflammatory function for C3a in vitro. Recently, C3a receptors have been cloned. These receptors are widely distributed on mast cells, neutrophils, basophils, eosinophils, and activated B cells. Deletion of the complement anaphylatoxin C3a receptor attenuates experimental autoimmune encephalomyelitis[6] and possibly depressive behavior.[7]

C5a receptors are expressed on neutrophils, macrophages, basophils, eosinophils, mast cells, and activated T cells, as well as on the epithelia of the proximal tubuli in the kidney, neurons, and glial cells. Activation of C5aR results in degranulation of cells, increased vascular permeability, and edema. In C5aR-deficient mice, the inflammatory response in the skin, lung, and peritoneum is reduced. Molecular modeling has shown possible conformations for the extracellular loops of the C5a receptors with mutations in the EC2 loop or in the EC3 loop, which may reflect general mechanisms of receptor constitutive activation.[8] C5a R2 deficiency diminishes activation of the NLRP3 inflammasome and the release of proinflammatory protein high-mobility group box 1 from macrophages both in vitro and in vivo.[9]

CR1 and CR2 deficiency have been found to increase coxsackievirus B3–induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, interleukin 1-1beta, and immune complex deposition in the heart.[4] C3aR deficiency may be protective against melanoma, implying a tumor-promoting role for C3aR signaling, at least in some murine models.[10]

Leukocyte adhesion deficiency type 1 (LAD-1) is an autosomal recessive disorder caused by mutations in the ITGB2 (CD18) gene and characterized by recurrent severe infections, impaired pus formation, and defective wound healing. Somatic revertant mosaicism may be seen with LAD-1.[11] A patient was described as a compound heterozygote bearing 2 different frameshift mutations that abrogate protein expression. Leukocyte adhesion deficiency type III is caused by mutations in KINDLIN3, affecting integrin activation.[12] While LAD-I patients experience recurrent bacterial infections, those with LAD-III have symptoms of both LAD-I and Glanzmann thrombasthenia.

Etiology

Both genetic and acquired factors have been associated with complement receptor deficiencies.

Epidemiology

Frequency

Partial or complete deficiencies in all components of the complement, as well as its regulatory proteins and receptors, were described in a relatively small number of patients in association with autoimmune or infectious diseases. The deficiencies were either inherited or acquired.

Leukocyte adhesion deficiency type 1 is said to affect 1 in 1 million people yearly.[13]

Race

No specific racial pattern is noted.

Sex

Receptor deficiencies associated with autoimmune disorders (eg, SLE) are more common in women than in men.

Age

Individuals of all ages may be affected. Reduced numbers of cellular receptors are present in preterm and stressed neonates. The leucocyte adhesion deficiency syndrome associated with deficiencies of CR3 and CR4 occurs mainly in children.

Prognosis

The prognosis may be guarded in severe cases. Complement plays a major role in the modulation of immune complex formation and its deposition, leading to tissue injury. Deficiencies in complement receptors are associated with a high frequency of immune complex diseases and infections. No predisposition to lymphoreticular malignancies is reported.

 

Presentation

History

In 1980, Fearon[14] originally identified and determined the molecular structure of the human CR1 receptor on red blood cells. This finding was followed by the discovery of 3 other cellular receptors for C3b and its degradation products: iC3b, C3dg, and C3d.

Genetic and acquired deficiencies of complement receptors were described only recently; they are associated with autoimmune disorders and infections. Deficiencies in CR1 and CR2 are mainly associated with SLE and other autoimmune dysfunctions. Human CR2, a B-cell membrane glycoprotein that plays a central role in autoimmunity, is reduced in SLE; a complete deficiency of CR2 and CR1 promotes the development of anti-DNA antibodies in mouse models of SLE.[15]

No complete deficiency is described, but reduced expression has been reported in humans. Whether they represent an inherited or acquired phenomenon is unclear, but findings tend to support the acquired phenomenon theory. Deficiencies in CR3 and CR4 have been observed in the leukocyte adhesion syndrome, which is inherited in an autosomal recessive fashion. C3aR and C5aR receptor deficiencies have been studied mainly in complement knockout mice and guinea pigs.

Physical Examination

Reduction in the number of complement receptors and immature host defenses in preterm newborns

Host defenses in neonates are not fully developed, and defective chemotaxis is believed to play a role. Neutrophils in preterm newborns have significantly fewer receptors for complement factors C3b (CR1/CD35) and iC3b (CR3) than neonates born at term or in adults. Also, C5aR receptor expression is reduced in preterm neonates.

CR1 and/or CR2 receptor deficiency in SLE and other conditions

SLE in humans is associated with abnormal B-cell functions and circulating autoantibodies probably caused by a dysregulation in B-cell tolerance. A rare acquired form of CR1 deficiency was documented in systemic lupus erythematosus associated with autoantibodies against CR1.[16]

In patients with severe SLE, expression of CR1/CD35 on erythrocytes is reduced to about one half of that of healthy individuals. This finding is correlated with disease activity. CR1 receptors are absent on the glomerular podocytes of patients with proliferative glomerulonephritis.

Mice with a deficiency in CD35/21 develop severe SLE with glomerulonephritis and have high amounts of double-stranded DNA (dsDNA) and antinuclear antibodies.

Fluctuating levels of CR1 are not unique to SLE. Decreased numbers of CR1 receptors on erythrocytes is also reported in other autoimmune disorders or diseases with complement activation, such as lepromatous leprosy, autoimmune hemolytic anemias, juvenile rheumatoid arthritis, and Sjögren syndrome.

Low numbers of CR1 receptors on red blood cells, as well as decreased expression of CR1 on erythrocytes and neutrophils, are also found in patients with AIDS. Their presence is correlated with more advanced disease.

Complement is implicated in the pathogenesis of not only autoimmune disorders but also organ failure due to sepsis, trauma, and burns.[17] Under physiological conditions, regulatory proteins and cellular receptors such as CR1/CD35 prevent uncontrolled activation of complement. In numerous animal models, recombinant soluble CR1 significantly reduced complement-mediated tissue damage and prolonged the survival of heart and kidney transplants in pretreated recipients. Recombinant soluble CR1 is well tolerated in humans, and its therapeutic potential has been evaluated in adults with respiratory distress syndrome and myocardial infarction.

Leukocyte adhesion deficiency and CR3 and/or CR4 receptor deficiency

An autosomal recessive inherited deficiency of the leukocyte beta2 integrin receptor CD11/18 is known as the leukocyte adhesion deficiency syndrome. It is associated with recurrent cutaneous infections and gingivitis. Leukocyte adhesion deficiency I was described in a patient with painful recurrent leg ulcers resembling pyoderma gangrenosum.[18] The syndrome is characterized by absent or reduced expression of leukocyte antigens CR3, LFA1 and CR4, or P150,95 and impaired neutrophil adhesive functions (eg, margination, chemotaxis, iC3b-mediated opsonization, phagocytosis). The defect is heterogeneous in that the severity of the disease parallels the degree of deficiency. The more severe forms are due to defects in gene encoding the common beta chain. Heterozygote individuals do not have a predisposition to infections, and their neutrophilic function is normal.

The following conditions are associated with newborns who are affected: delayed separation of the umbilical cord and secondary omphalitis, severe recurrent Staphylococcus aureus and gram-negative bacterial infections, periodontitis, impaired wound healing, lack of pus formation, and leukocytosis.

C3aR and C5aR receptor deficiency

To the author's knowledge, only animal studies have been performed at this time.

C3a has been implicated in the development of adult respiratory distress syndrome or multisystem failure in patients with toxic shock syndrome. The protective role of receptor C3aR in septic shock has been shown in mice with targeted homozygous gene deficiency for C3aR (C3aR-/-). An increased susceptibility to shock was observed in these mice and associated with increased levels of tumor necrosis factor-alpha and interleukin 6.

C3a and its receptor C3aR also have a pivotal role in the pathogenesis of allergy-induced responses, such as bronchoconstriction in asthma, as demonstrated in guinea pigs with a natural C3aR defect or in genetically engineered C3aR knockout mice.[19]

In C5aR-deficient mice, the inflammatory response is decreased in skin, lung, and peritoneum.

Blocking the C5a receptor may be a good alternative to high-dose corticosteroids in treating ANCA-associated vasculitis.[20]

Complications

Complications may be life threatening in severe cases. Complications include problems associated with underlying autoimmune disorders and life-threatening systemic bacterial infections in some patients with the leukocyte adhesion deficiency syndrome.

 

DDx

 

Workup

Laboratory Studies

Tests for CD35 and CD21 markers for receptors CR1 and CR2 are usually not performed in patients with SLE or other autoimmune disorders because their reduction is more a result of active disease than a cause of the disease.

CD11a/18, CD11b/18, and CD11c/18 markers can be used to identify CR3 and CR4 deficiencies in the leukocyte adhesion deficiency syndrome.

Other laboratory tests may be ordered, on the basis of the associated or underlying disease.

 

Treatment

Medical Care

No specific treatment is required for complement receptor deficiencies, other than symptomatic treatment for associated autoimmune disorders or recurrent infections.

Systemic steroids and steroid-sparing agents may be required for the treatment of deficiencies associated with immune disorders. Prophylactic and therapeutic antibiotics may be prescribed as needed. The value of avacopan, an oral C5a receptor inhibitor, in patients with ANCA-associated vasculitis is being accessed.[21]

Bone marrow transplantation may be of help in severe cases of leukocyte adhesion deficiency syndrome. Hematopoietic stem-cell transplantation is of long-term benefit and an early therapeutic option with a suitable HLA-matched stem cell.[22] Another approach is the use of ustekinumab, an antibody that binds the p40 subunit of interleukin 23 and interleukin 12.[23]

Hospitalization may be required in cases associated with severe autoimmune disorders and systemic involvement, as well as in cases with severe infections.

Consultations

In patients with severe SLE or other autoimmune disorders, referral to a rheumatologist or an internist may be advised.

In patients with leukocyte adhesion deficiency syndrome, a pediatrician and an infectious diseases specialist is needed in the neonatal period.

Long-Term Monitoring

Patients need to be monitored on a regular basis.

 

Medication

Medication Summary

Systemic steroids, immunosuppressive drugs, or medications adapted to the underlying disorder may be required in patients with autoimmune dysfunctions. Adapted antibiotics should be prescribed for the treatment of recurrent infections associated with the leukocyte adhesion syndrome deficiency.

 

Questions & Answers